Abstract: Background and Objective: Rheumatoid arthritis causes an elevated risk for Osteoporotic Fractures (OP). The present study aimed to investigate the risk for osteoporotic fractures on the combined use of methylprednisolone and Proton Pump Inhibitors (PPIs) among Chinese rheumatoid arthritis patients. Materials and Methods: A total of 4993 RA patients age between 55-75 were administered and exposure with methylprednisolone and proton pump inhibitors were investigated for the risk for osteoporotic fractures (OR). The exposure was stratified by the use of methylprednisolone and PPIs such as omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole and control (non-users). These subjects have been using the drugs for more than 24 months and above. Results: The combined users of methylprednisolone and PPIs had a mean age of 69.22 years compared to the 65.54 years of control. The combined users were linked with a 1.5 fold increased risk for OR compared with the control (OR = 1.56 (95% CI: 1.42-1.93)). It is observed that the OR fracture in the combined users had a 1.5 fold higher risk for hip fracture (OR = 1.52 (95% CI: 1.22-1.87), 3 fold higher risk for vertebral fracture (OR = 2.95 (95% CI: 1.92-4.27)), a 2.5 higher risk for pelvis fracture (OR = 2.51 (95% CI: 1.36-4.27)) and 4.1 higher risk for rib fracture (OR = 4.13 (% CI: 2.24-7.56)) compared to the control. Conclusion: There is an association in the risk for OR fracture between the combined use of methylprednisolone and PPIs due to the biological mechanism of action between methylprednisolone and PPIs on the bone of the RA patients.
INTRODUCTION
Rheumatoid arthritis is a chronic disease that affects joints such as the knees, feet, spine, wrist, hands and caused an elevated risk for osteoporotic (OP) fractures1. The RA is also marked by symptoms of inflammation, pain in the joints and the immune system of the body also attacks its tissue including joints2. RA is an autoimmune and inflammatory disease, which indicates that the immune system of the human body attacks healthy cells by mistake3. The cause of the immune system malfunction in RA is not fully understood whereas some individuals develop RA due to genetic factors4. In RA, the antibodies of the human immune network attack the synovium, or the smooth membrane of the joints which results in pain of the joints and inflammation5. The inflammation thus results in the thickening of the synovium and in course of time off left untreated destroys the cartilage and connective tissue thereby causing osteoporotic (OP) fractures6,7. The RA can be treated with certain medicines and self-management effectively. The treatments available for RA in the market are analgesics, Corticosteroids, Disease-modifying anti-rheumatic drugs (DMARDs) and Non-steroidal anti-inflammatory drugs (NSAIDs)7. However, the medicines for RA such as glucocorticoids (GCs) are also in grave concern for increased fracture risk due to their inflammatory process and its pharmacological treatment. In China, many RA elderly patients are currents users of oral GCs especially methylprednisolone8,9. Patients undergoing treatment with oral methylprednisolone have a tendency of developing bone mineral density (BMD) in the hip region and vertebrae thereby increasing the risk for fracture10. Among the oral methylprednisolone users, many patients were also observed with poor bone density followed by reduced bone formation and inclined bone resorption11,12. In addition, to methylprednisolone, RA patients are regularly frequently prescribed and administered with certain medications such as Non-steroidal anti-inflammatory drugs (NSAIDs) and Proton Pump Inhibitors (PPIs) such as omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole to control gastrointestinal disorders. There are also reports which observed that patients undergoing medications with NSAID and PPI also lead to bone weakness and fractures apart from methylprednisolone and in many cases, these drugs are co-administered together13. To date, there are no such studies in China in RA patients evaluating the risk of simultaneous use of methylprednisolone and PPIs in elderly patients. Therefore, the present study was an attempt to investigate the association of methylprednisolone and Proton Pump Inhibitors (PPIs) and their risk for osteoporotic fractures among Chinese patients with rheumatoid arthritis.
MATERIALS AND METHODS
Ethical statement: All experiments were performed according to guidelines of the Declaration of Helsinki 1964 and its later amendments. Written consent was taken from all the subjects. Permission and approval were taken about their details, demographic factors, medical episodes, drinking and smoking habits using a standard questionnaire. The study was approved by the Research Review and Ethics Board (RREB) of Yan’an University Affiliated Hospital.
Study design and population: The study population consists of 4993 RA patients enrolled in the Hospital from September, 2015 till October, 2020. The study subjects were mostly exposed to Oral methylprednisolone and PPIs. The study also includes data on patient’s population characteristics, clinical records, drug administration details and laboratory findings. Patients between 55-75 years and who were administered with oral methylprednisolone and PPIs for years were included in the study.
Main exposures and outcome: Rheumatoid arthritis Patients in the age between 55-75 who were administered and exposed with methylprednisolone (methyl) and Proton Pump Inhibitors (PPIs) viz. esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole were investigated for the study. The RA patients were further categorized and divided into four different groups viz. Group A (methylprednisolone+PPIs users), Group B (methylprednisolone users), Group C (PPIs users) and Group D (Control, which is a non-user of methylprednisolone and PPIs). The prescription and administration details of each drug were recorded including their dosage and time duration. Group A users were defined as the use of methylprednisolone and one PPI (either Omeprazole, Lansoprazole, Rabeprazole, Esomeprazole, Pantoprazole). Group B users were defined as the use of methylprednisolone only. Group C (PPI alone users) users were defined as the use of one PPI only either omeprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole). Group D (Control, which is a non-user of methylprednisolone and PPI) were defined as those patients who were not administered with methylprednisolone and PPIs. Patients who were administered with more than one PPI inhibitor were not included in the investigation from the study. Follow-up continued for all the participants till the completion of the investigation. The main outcome of the investigation was osteoporotic fracture (OP) as a result of osteoporosis, in which the bones become fragile due to deterioration of the bone mass. The index of OP fracture includes forearm, hip, humerus, pelvic, rib and vertebral fractures.
Statistical analysis: SPSS 17.0 package was used for performing the statistical analysis (SPSS Inc, USA). The association between methylprednisolone users, PPI and the risk for OP fractures were evaluated by including assessing the confounders. The statistical significance of the patients was investigated based on the exposed confounders such as BMI, smoking and drinking status, history of comorbidities, etc. The strength of the association, Odds Ratios (OR) were estimated using multivariable logistic regression to approximation at 95% Confidence Intervals (CI) to analyze the association of combined usage of methylprednisolone and PPIs for their OP fracture risk. Non-user of methylprednisolone and PPIs were considered as the control.
RESULTS
In the present study, 4993 RA patients were included. The combined users of Met and PPI had a mean age of 69.22 compared to 68.31 of Met users, 66.71 of PPI users and 65.54 of control in Table 1. Whereas the population of RA women patients with combined users was 1169 (61.43%) compared to 581 (63.71%) methyl users, 667 (62.39%) of PPI users and 692(62.40%) of control (Table 1).
| Table 1: Characteristics of investigated rheumatoid arthritis (RA) population (N = 4993) | ||||
| Characteristics | Combined user of methyl+PPI (N = 1903) n (%) |
Methyl users (N = 912) n (%) |
PPI users (N = 1069) n (%) |
Control (N = 1109) n (%) |
| Age (years), Mean SD | 69.22 |
68.31 |
66.71 |
65.54 |
| Female | 1169 (61.43) |
581 (63.71) |
667 (62.39) |
692 (62.40) |
| BMI (kg m–2) | ||||
| Normal (18.5-24.9) | 654 (34.37) |
326 (35.75) |
412 (38.54) |
489 (44.09) |
| Overweight (25.0-29.9) | 830 (43.62) |
389 (42.65) |
440 (41.16) |
411 (37.06) |
| Obesity (<30) | 419 (22.02) |
197 (21.60) |
217 (20.30) |
209 (18.85) |
| Smoking status | ||||
| Non-smoker | 684 (35.94) |
333 (36.51) |
436 (40.79) |
452 (40.76) |
| Present | 459 (24.12) |
235 (25.77) |
239 (22.36) |
259 (23.35) |
| Past | 760 (39.94) |
344 (37.72) |
394 (36.86) |
398 (35.89) |
| Alcohol use | ||||
| Non-user | 558 (29.32) |
300 (32.89) |
304 (28.44) |
304 (27.41) |
| Regular user | 1345 (70.68) |
612 (67.11) |
765 (71.56) |
805 (72.59) |
| Comorbidities | ||||
| Asthma | 249 (13.08) |
115 (12.61) |
64 (5.99) |
76 (6.85) |
| Anemia | 237 (12.45) |
102 (11.18) |
126 (11.79) |
131 (11.81) |
| Cerebrovascular disease | 103 (5.41) |
45 (4.92) |
54 (5.05) |
51 (4.60) |
| Chronic renal failure | 66 (3.47) |
31 (3.40) |
30 (2.81) |
38 (3.43) |
| Congestive heart failure | 47 (2.47) |
33 (3.62) |
24 (2.25) |
44 (3.97) |
| COPD | 148 (7.78) |
74 (8.11) |
28 (2.62) |
35 (3.16) |
| Diabetes (type 2) | 109 (5.73) |
50 (5.49) |
66 (6.17) |
58 (5.23) |
| Gastro-oesophagael reflux disease | 92 (4.83) |
39 (4.28) |
53 (4.96) |
37 (3.34) |
| Hypothyroidism | 128 (6.73) |
71 (7.79) |
78 (7.30) |
75 (6.76) |
| Ischemic heart disease | 227 (11.93) |
108 (11.84) |
116 (10.85) |
138 (12.44) |
| Malignant neoplasm’s | 168 (8.83) |
82 (8.99) |
87 (8.14) |
82 (7.39) |
| Major infections | 349 (18.34) |
171 (18.75) |
164 (15.34) |
157 (14.16) |
| Peripheral arterial disease | 87 (4.57) |
48 (5.26) |
51 (4.77) |
46 (4.15) |
| Comedications | ||||
| Anticoagulants | 56 (2.94) |
29 (3.18) |
18 (1.68) |
39 (3.52) |
| Anticonvulsants | 26 (1.37) |
20 (2.19) |
12 (1.12) |
17 (1.53) |
| Antidepressants | 214 (11.25) |
112 (12.28) |
105 (9.82) |
101 (9.11) |
| Antihypertensive | 624 (32.79) |
316 (34.65) |
351 (32.83) |
369 (33.27) |
| Bisphosphonate | 115 (6.04) |
36 (3.95) |
41 (3.84) |
41 (3.70) |
| Calcium/vitamin D | 126 (6.62) |
46 (5.04) |
50 (4.68) |
64 (5.77) |
| Hormone replacement therapy | 81 (4.26) |
26 (2.85) |
38 (3.55) |
35 (3.16) |
| Hypnotics/anxiolytics | 162 (8.51) |
77 (8.44) |
72 (6.74) |
63 (5.68) |
| Severity of diseases | ||||
| COX-2 selective inhibitors | 182 (9.56) |
94 (10.31) |
96 (8.98) |
78 (7.03) |
| Non-selective NSAIDs | 853 (55.19) |
521 (57.13) |
579 (54.16) |
548 (50.59) |
| csDMARDs | 559 (29.37) |
265 (29.06) |
357 (33.40) |
379 (34.17) |
| Opioids | 105 (5.52) |
52 (5.70) |
45 (4.21) |
44 (3.97) |
| Paracetamol | 922 (48.45) |
418 (45.83) |
434 (40.60) |
478 (43.10) |
| Tramadol | 121 (6.36) |
60 (6.58) |
59 (5.52) |
49 (4.42) |
Methyl: Methylprednisolone, PPI: Proton pump inhibitors, BMI: Body mass index, COPD: Chronic obstructive pulmonary disease, COX-2: Cyclooxygenase-2, NSAID: Nonsteroidal anti-inflammatory drug, csDMARD: Conventional synthetic disease-modifying antirheumatic drugs |
||||
| Table 2: Risk assessment analysis for OP fracture based on the combined use of methylprednisolone and proton pump inhibitors (PPIs) | ||||
| Users | Osteoporotic fractures (n = 1192) |
Incidence rate (1000/person years) |
Odds ratio (adjusted for age and sex, 95% CI) |
Odds ratio (adjusted for full, 95% CI) |
| Control | 321 |
11.39 |
Reference |
Reference |
| Combined methyl and PPI users | 349 |
28.15 |
1.88 (1.71-2.35) |
1.56 (1.42-1.93) |
| Methyl users | 226 |
16.56 |
1.28 (1.09-1.64) |
1.19 (1.12-1.56) |
| PPIs users | 296 |
18.21 |
1.35 (1.26-1.67) |
1.17 (1.12-1.55) |
OP: Osteoporotic fractures, Methyl users: Methylprednisolone users, PPIs users: Proton pump inhibitors users |
||||
Based on the BMI analysis, 419 (22.02%) of the combined users were obese and 830(43.62%) were overweight, whereas 654 (34.37%) had a normal BMI. However, the control user had a normal BMI of 489 (44.09%) having a 1.2 fold increase compared to combined users. There was not much variation on the status of smoking and alcohol use among the investigated groups. Moreover, no significant differences were observed between the combined users and the control as well as the users of methyl and PPI based on the comorbidities. However, the combined users had a higher major infection rate of 349 (18.34%) compared to 157 (14.16%) of the control. The study also observed that 853 (55.19%) of the combined users had taken Non-selective NSAIDs compared to 548 (50.59%) of the control. Out of the total 4993 RA patients, 1192 patients were experienced with osteoporotic fractures in Table 2. The combined users of methyl and PPIs among the RA patients were linked with a 1.5 fold higher possibility for osteoporotic fracture in comparison to the control (OR = 1.56 (95% CI: 1.42-1.93)) with an incidence rate of 28.15 compared to 11.39 of the control (Table 2). On the other hand, both methyl users and PPI users had a 1.1 fold increase possibility for OP fracture (OR = 1.19 (95% CI: 1.12-1.56) for Met users; OR = 1.17 (95% CI: 1.12-1.55)). In Table 3, it is observed that the osteoporotic fracture in the combined users had a 1.5 fold higher risk for hip fracture compared to the control (OR = 1.52 (95% CI: 1.22-1.87) with an incidence rate of 5.8 times compared to the control. The combined users also had a 3 fold higher possibility for vertebral fracture (OR = 2.95 (95% CI: 1.92-4.27)), a 2.5 higher risk for pelvis fracture (OR = 2.51 (95% CI: 1.36-4.27)) and 4.1 higher possibility for rib fracture (OR = 4.13 (% CI: 2.24-7.56)) compared to the control.
DISCUSSION
The study observed that the simultaneous use of oral methylprednisolone and PPIs is linked with a higher chance of OP fractures compared to non-users among RA patients. The simultaneous use of methylprednisolone and PPIs also increases the risk and possibility of OP fractures among the RA patients compared to the control group. The study also observed that the combined use of methylprednisolone and PPIs was linked with a higher risk for rib, vertebrae, pelvis and hip. But it has a low risk of pelvis and forearm fracture. However, the study observed that the risk for OP fracture was not linked with the average daily dosage or higher daily dosage of the combined users. In the current study, apart from the combined users, the PPIs users also had a higher fracture risk compared to the control and the met users which is concurrence with several other observational studies14-16. It is also reported that the PPIs administration was connected with a 1.2 fold higher risk of hip and femur fracture which is due to the positive association which is because of its continuous use17. Moreover, it is also reported that the use of PPI is associated with an increased risk of hip, spine and any-site fractures compared to histamine2-receptor antagonists (H2RAs) users among non-RA patients18. In another study by Yuan et al.19, it is reported that the regular use of PPI was associated with fractures, gastric cancer and other health problems among women. They further reported that PPIs have a significant impact on the gut microbiome thereby increasing the risk of RA19. On the other hand, it is further reported that the use of GC such as methylprednisolone increases the risk for OP fracture in RA patients20. The GC exposure was also associated with excess fracture risk concerning increasing dose, duration and duration of exposure20,21. Moreover, various studies reported on the effect of glucocorticoids on fracture risk in RA patients but no clear consensus about the magnitude of risk could be finalized. It is estimated the risk for fracture are complicated by the dynamic pattern of glucocorticoid use such as consideration of dose, timing and duration21,22. However, in the current study, a unique reference group which is both non-users of methylprednisolone and PPIs is added to explain the statistical significance compared to methylprednisolone users alone and PPIs users alone. In another study by Abtahi et al.8, it was reported that the concomitant administration of GCs and PPIs was linked with a 1.6-fold higher risk for OP fracture. The cause of the OP fracture may be due to the individual effect of the drugs instead of their synergistic effect23.
| Table 3: Risk assessment stratified by fracture type based on the combined use of methylprednisolone and Proton Pump Inhibitors (PPIs) | |||||
| By recency of use | Non-use of Methyl and PPIs |
Combined Methyl and PPI users |
Methyl users |
PPIs users |
|
| Hip (N=411) | Incidence Rate (1000/Person Years) |
4.2 |
8.7 |
5.9 |
6 |
Odds Ratio (Adjusted for full, 95% CI) |
Reference |
1.52 (1.22-1.87) |
1.31 (1.06–1.73) |
1.08 (0.76–1.35) |
|
| Clinical vertebral (N=179) | Incidence Rate (1000/Person Years) |
1 |
5.8 |
2.3 |
2.9 |
Odds Ratio (Adjusted for full, 95% CI) |
Reference |
1.28 (0.83–2.25) |
1.82 (1.19–2.74) |
||
| Humerus (N=293) | Incidence Rate (1000/Person Years) |
3.2 |
6.1 |
2.7 |
3.8 |
Odds Ratio (Adjusted for full, 95% CI) |
Reference |
1.32 (0.87–1.85) |
1.12 (0.76–1.58) |
1.22 (0.91–1.68) |
|
| Forearm (N=196) | Incidence Rate (1000/Person Years) |
1.8 |
3.5 |
2.7 |
2.9 |
Odds Ratio (Adjusted for full, 95% CI) |
Reference |
0.94 (0.66–1.29) |
1.26 (0.87–1.84) |
1.04 (0.81–1.45) |
|
| Pelvis (N=86) | Incidence Rate (1000/Person Years) |
0.7 |
3 |
1.2 |
1.8 |
Odds Ratio (Adjusted for full, 95% CI) |
Reference |
2.51 (1.36–4.27) |
1.12 (0.61–2.24) |
1.88 (1.21–3.41) |
|
| Rib (N=45) | Incidence Rate (1000/Person Years) |
0.8 |
1.5 |
1.4 |
1.1 |
Odds Ratio (Adjusted for full, 95% CI) |
Reference |
4.13 (2.24–7.56) |
2.32 (1.24–4.53) |
1.16 (0.75–2.27) |
|
Methyl users: Methylprednisolone users, PPIs users: Proton pump inhibitors users |
|||||
CONCLUSION
The study observed that the combined use of methylprednisolone and PPIs such as esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole among RA patients increases the risk for OP fracture. The study rules out that there is an interaction between the combined use of methylprednisolone and PPIs in which the biological mechanism may be due to the individual mechanisms of action of methylprednisolone and PPIs on the bone of the RA patients. Yet, a slight increase in the risk for fracture due to combined use of methylprednisolone and PPIs may lead to a higher number of OP fractures on a larger public health scale. Therefore, the study proposes that physicians counsel should avoid RA patients administering the combined use of methylprednisolone and PPIs for the risk for osteoporotic fracture.
SIGNIFICANCE STATEMENT
This study discovered that the combined use of methylprednisolone and PPIs causes osteoporotic fractures among RA patients which is due to the interaction between these drugs and their mechanisms of action. This study will help the physicians in avoiding the combined administration of methylprednisolone and PPIs.
ACKNOWLEDGMENT
The authors thank the Yan'an University Affiliated Hospital, Yan'an, Shaanxi, China-716000 for the research support and administrative support.